Gulf War Pesticide Metabolite-Mediated Autoimmune Dysfunction in Gulf War Illness
Abstract
Over 25 years after the 1990-1991 Gulf War (GW), 250,000 Veterans of that era still suffer from Gulf War Illness (GWI), a chronic and debilitating condition that presents with seemingly unrelated symptoms such as chronic fatigue, debilitating pain, and cognitive problems. To date, this illness remains difficult to diagnose and treat since exposure to GW chemicals happened nearly 30 years ago and many aspects of GWI pathology still remain undefined. Many studies now provide strong support that pesticide exposure during the GW is one of the key factors in causing GWI. Our recent work shows that the pesticides used during the 1991 GW can cause the body to react to its own molecules in a way that is characteristic of an autoimmune disease. This is supported by the fact that GWI Veterans show symptoms that could fit the profile of an autoimmune disease. The goal of the proposed study is to identify how GWI pesticides drive this autoimmune dysfunction. Once the mechanism has been identified, novel biomarkers that are specific to GWI pesticide exposure can be identified and new means of intervention for GWI Veterans can be developed. Until now, this hypothesis of autoimmunity in GWI has been dismissed because GW pesticides and their subsequent products, known as metabolites, are too small by themselves for the immune system to register as a threat. However, if those molecules combine with native proteins, the combination is called a hapten and a combination of native protein and pesticide can become large enough to be registered by the immune system. This prompts the immune system to attack its own proteins, since its own native proteins were registered as foreign threats. Our studies show that some of the common metabolites of GW pesticides do form haptens and subsequently prompt the immune system to send white blood cells (also known at T- and B-cells) to attack the haptens and native proteins. We found that autoantibodies, which are flags that the immune system uses to mark foreign threats, specific to those haptens are present in our well-characterized GWI mouse model long after the initial pesticide exposure. We also observed these autoantibodies in Veterans diagnosed with GWI nearly 30 years after they would have been originally exposed, thus corresponding with their self-reports of pesticide exposure. These immune changes also corresponded with increased inflammation and white blood cells in the brains of GWI mice despite the existence of a barrier between the brain and the blood/peripheral body systems, which is intended to keep the white blood cells from the periphery out of the brain. This evidence of pesticide exposure activating immune responses in both the brain and peripheral body systems, along with the fact that GWI Veterans show autoimmune symptoms, supports further examination of the role of hapten-associated autoantibodies in GWI. We hypothesize that GW metabolites form haptens with native proteins and activate peripheral immune cells, resulting in the production of autoantibodies against haptenated proteins. These autoantibodies may enter the brain and cross-react with normal brain proteins, promoting central nervous system damage and inflammation in the brain. Certain types of white blood cells, known as memory B-cells and plasma cells (PC) that can linger in the body for decades, are known to be very specific in their ability to target a specific antigen. Therefore, we anticipate that these cells are involved in the chronic and persistent autoimmune response to GW pesticide haptenated proteins. The primary objective of the proposed work is to identify autoantibodies against haptenated GW pesticides at time points long after the initial exposure in both the GWI mouse models and also in Veterans with GWI. We will also investigate whether these autoantibodies can enter the brain and attack brain proteins and whether memory B-cells and PC are involved in the GWI pesticide hapten-induced CNS d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010809
Entities
People
- Laila Abdullah
Organizations
- Roskamp Institute
- United States Army